Changes in gut microbiota and plasma metabolites in patients with symptomatic degenerative rotator cuff tendinopathy.

OBJECTIVE: To investigate alterations in gut microbiota and plasma metabolites in patients with symptomatic degenerative rotator cuff tendinopathy (dRCT), and to explore potential microbiota-mediated metabolic mechanisms involved in tendon degeneration. METHODS: A case-control study with group-level matching for age, sex, and BMI was conducted, including 61 patients with symptomatic dRCT confirmed by clinical examination and magnetic resonance imaging and 61 healthy controls matched for age, sex, and body mass index. One RCT participant was subsequently excluded from all the final analyses due to insufficient sample volume. Fecal and plasma samples were collected for 16S rRNA amplicon sequencing and untargeted metabolomic analysis. PICRUSt2-based microbial functional prediction and microbiota-metabolite correlation analysis were performed to characterize gut microbial and metabolic alterations associated with dRCT. RESULTS: Gut microbiota β-diversity differed significantly between dRCT patients and controls (P = 0.014). LEfSe analysis showed that the dRCT group was enriched in Bacteroidota and Pseudomonadota, as well as genera including Segatella, Megamonas, Klebsiella, Desulfovibrio, Agathobacter, and Alistipes. In contrast, controls were enriched in Bacillota and short-chain fatty acid-producing genera, including Gemmiger and the Eubacterium_ruminantium group. PICRUSt2 prediction indicated upregulation of pro-inflammatory microbial pathways in dRCT, including lipopolysaccharide biosynthesis, flagellar assembly, vitamin B6 metabolism, and riboflavin metabolism, whereas controls showed higher activity in amino acid synthesis and tissue repair-related pathways, including valine/leucine/isoleucine biosynthesis, lysine biosynthesis, and cysteine and methionine metabolism. Untargeted metabolomics identified 309 differential metabolites in positive ion mode and 226 in negative ion mode. KEGG enrichment revealed significant alterations in tryptophan metabolism and ferroptosis pathways in positive ion mode, and changes in unsaturated fatty acid biosynthesis, bile secretion, tryptophan metabolism, and steroid hormone biosynthesis in negative ion mode. Correlation analysis showed that Segatella and Megamonas were negatively correlated with indole-3-acetaldehyde and vitamin E, while Gemmiger was positively correlated with Quininic acid. CONCLUSION: To our knowledge, this is the first human multi-omics study systematically investigating the potential "gut-tendon axis". Patients with dRCT exhibited gut microbiota dysbiosis characterized by enrichment of pro-inflammatory bacteria and a divergent shift among SCFA/butyrate-producing bacteria, with net depletion of the predominant taxa. These alterations may be associated with tendon degeneration through gut-derived endotoxin production, reduced tryptophan-to-indole conversion capacity, and ferroptosis-related oxidative stress.